It has been empirically known that stress induces disorders; however, the pathway by which stress disrupts host defense was not clarified and there was no means to objectively assess stress response. In this research project, we investigated (1) molecular basis for stress-induction of interleukin (IL) -18, (2) plasma levels of cytokines and chemokines in mice exposed to experimental stress, and (3) a role of IL-18 in stress-activation on hypothalamic-pituitary-adrenal axis, and (4) established a protein-array system for cytokines determination. Here we showed that (1) acute immobilization stress activates caspase-1 via NADPH oxydase in the adrenal cortex to cause IL-18 secretion into blood, (2) distinct plasma levels of cytokines and chemokines are formed in mice exposed to immobilization or isolation, demonstrating that cytokines are not a case of general adaptation syndrome, (3) IL-18 is involved in an activation of hypothalamic-pituitary-adrenal axis after stress, mediating a feedba
… Moreck loop for sustained activation of hypothalamic-pituitary-adrenal axis, and (4) reproducible and accurate determination for cytokines from a few amount of plasma samples. These elucidations indicate that IL-18 is a connecting molecule for immue, endocrine, and neural systems, playing a pivotal role in homeostatic response of host defense, and that severe stress causes hyper-activation of the IL-18 system, which may lead to a disrupted network for host defenses. Further, cytokines and chemokines concentrations in plasma are suggested to be a possible biomarkers for duration, severity, context, and risk of stressors. Together with the findings that stress induces psychological and psychiatric abnormalities via hypothalamic-pituitary-adrenal axis, our finding suggest that investigation on cytokines in stress response may provide a possible therapeutic means for stress-related diseases, such as depression, FTSD, schizophrenia, autoimmune diseases, metabolic syndromes, and cardiomyopathy. Based on the findings, a study to clarify a molecular basis for stress-related cytokines inducing cascade has been started. Less